The present invention is concerned with the regulation of intra-ocular pressure (IOP), and is more particularly concerned with the reduction of elevated IOP.
The ion transport mechanisms underlying fluid balance within the eye and the maintenance of intra-ocular pressure (IOP) are poorly understood. Aqueous humour (abbreviated to aqueous hereinafter) is produced by the ciliary epithelium, a complex bi-layer consisting of an inner non-pigmented epithelial layer in direct contact with the aqueous and an outer pigmented epithelial layer adjacent to the highly vascularised connective tissue stroma of the ciliary processes. Aqueous circulates from the posterior chamber into the anterior chamber and is drained predominantly through the trabecular meshwork into Schlemm""s canal, and to a lesser extent through the uveoscleral pathways. The production of aqueous is dependent on several mechanisms: active transport, carbonic anhydrase inhibition, diffusion and ultrafiltration. IOP is dependent upon the relative rates of formation and drainage of the aqueous.
It is known that the membrane-bound enzyme complex Na+/K+ ATPase (sodium potassium adenosine triphosphatase) in the non-pigmented ciliary epithelium has an important role in the active secretion of aqueous. In other tissues (e.g. kidney, colon and salivary gland) sodium transport is facilitated by the stimulation of Na+/K+ ATPase by adrenocorticosteroids, such as glucocorticoids (e.g. cortisol) or mineralocorticoids (e.g. aldosterone). In these tissues, corticosteroid hormone action is regulated by 11-xcex2-hydroxysteroid dehydrogenase (11-xcex2-HSD). Two isoforms of the enzyme are known: 11-xcex2-HSD1, a NADP(H)-dependent enzyme acting primarily as an oxo-reductase in vivo (catalysing the conversion of inactive cortisone to hormonally active cortisol, and references hereinafter to a xcex2-HSD-1 inhibitor are intended to relate to the inhibition of this oxo-reductase activity), and 11-xcex2-HSD2, a high affinity NAD-dependent dehydrogenase (catalysing the conversion of cortisol to hormonally inactive cortisone). In the kidney, sodium transport is predominantly regulated by 11-xcex2-HSD2, as demonstrated by the ingestion of carbenoxolone (a potent 11-xcex2-HSD1 and 11-xcex2-HSD2 inhibitor) which results in increased levels of cortisol and cortisol-mediated renal sodium retention.
It is also known that the eye is an important target tissue for corticosteroids. Both mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) have been demonstrated in the eye, as well as a number of steroid hormones within the aqueous (including cortisol and aldosterone). Corticosteroids are implicated in the natural diurnal variation of IOP. The variation is attributable to changes in the rate of aqueous formation which varies synchronously with endogenous circulating cortisol and catecholamines. Glucocorticoids also cause an increase in IOP secondary to a decrease in the facility of aqueous outflow (corticosteroid-induced glaucoma). The majority of such cases are secondary to exogenous use of corticosteroids (systemic, topical or periocular), but some cases arise from abnormal endogenous corticosteroid production (e.g. Cushings syndrome).
However, little is known about the role of corticosteroids in the regulation of aqueous production.
It is an object of the present invention in at least one aspect, to provide a medicament capable of lowering intra-ocular pressure.
In a first aspect, the present invention resides in the use of a xcex2-HSD-1 inhibitor for the manufacture of a pharmaceutical composition for lowering intra-ocular pressure.
According to a second aspect of the present invention, there is provided a pharmaceutical composition suitable for topical administration to an eye, said composition comprising a xcex2-HSD-1 inhibitor and a pharmaceutically acceptable diluent or carrier suitable for administration to the eye.
According to a third aspect of the present invention, there is provided a method of reducing intra-ocular pressure (IOP) in a patient afflicted with elevated IOP, comprising the step of administering (preferably topically to an afflicted eye) to the patient a therapeutically effective amount of a xcex2-HSD-1 inhibitor.
The various aspects of the present invention are based on the discovery by the Inventor that 11-xcex2-HSD1 and 11-xcex2-HSD2 are present in the eye, and that surprisingly 11-xcex2-HSD1 has a much higher activity in the eye than 11-xcex2-HSD2, such that Na+/K+ ATPase-moderated aqueous production is primarily regulated by 11-xcex2-HSD1 rather than 11-xcex2-HSD2. This is contrary to what would have been expected from other target tissues. Said elevated IOP may be as a result of exogenous corticosteroid administration, or as a result of disease (e.g. glaucoma and Cushing""s syndrome), although it will be understood that the actual cause of elevated IOP is immaterial to the effectiveness of the invention.
Said xcex2-HSD-1 inhibitor may be provided by liquorice or a derivative thereof (e.g. glycyrrhetinic acid or carbenoxolone). Alternatively, said xcex2-HSD-1 inhibitor may be progesterone or a derivative thereof (e.g. 11xcex1-hydroxy or 11xcex2-hydroxy progesterone). Preferably, said xcex2-HSD-1 inhibitor is carbenoxolone. It will be understood that said 11-xcex2-HSD1 inhibitor may also be an 11-xcex2-HSD2 inhibitor.